Effect of ketoconazole on the 11-hydroxylation step of adrenal steroidogenesis

We studied the effect of ketoconazole on glucocorticoid metabolism in three patients before and after a continuous four-hour infusion of ACTH. A single 400 mg oral dose of ketoconazole caused a decrease in serum cortisol concentration, while the concentration of 11-deoxycortisol and its ratio to cortisol increased. The decrease in serum cortisol levels was not accompanied by an increase in plasma ACTH concentration. A four-hour continuous infusion of ACTH resulted in an appropriate elevation of serum cortisol, but with a marked increase in serum concentration of 11-deoxycortisol and its ratio to serum cortisol. We conclude that 400 mg of ketoconazole can decrease cortisol synthesis apparently through a partial block of the 11-beta-hydroxylation step; the observed degree of inhibition may not be sufficient to stimulate the hypothalamic-pituitary-adrenal axis or to cause overt symptoms or signs of adrenal insufficiency; and this partial block of the 11-beta-hydroxylation step becomes more evident during a continuous infusion of ACTH, which can stimulate a normal response of cortisol.